The benzimidazole and imidazopyridine derivatives of the present invention are sodium channel modulators. In particular they are modulators of the Nav1.8 sodium channel. Preferred benzimidazole and imidazopyridine derivatives of the invention show an activity for the Nav1.8 channel which is greater than their activity for other sodium channels such as the Nav1.5 sodium channel and the tetrodotoxin-sensitive sodium channels (TTX-S). The benzimidazole and imidazopyridine derivatives of the invention have a number of therapeutic applications and potential therapeutic applications. In particular they are useful in the treatment of pain.
Voltage-gated sodium channels are found in all excitable cells including myocytes of muscle and neurons of the central and peripheral nervous system. In neuronal cells, sodium channels are primarily responsible for generating the rapid upstroke of the action potential. In this manner sodium channels are essential to the initiation and propagation of electrical signals in the nervous system. Proper and appropriate function of sodium channels is therefore necessary for normal function of the neuron. Consequently, aberrant sodium channel function is thought to underlie a variety of medical disorders (see Hubner C. A., Jentsch T. J., Hum. Mol. Genet., 11(20): 2435-45 (2002) for a general review of inherited ion channel disorders) including epilepsy (Yogeeswari et al., Curr. Drug Targets, 5(7): 589-602 (2004)), arrhythmia (Noble D., Proc. Natl. Acad. Sci. USA, 99(9): 5755-6 (2002)), myotonia (Cannon, S. C., Kidney Int. 57(3): 772-9 (2000)), and pain (Wood, J. N. et al., J. Neurobiol., 61(1): 55-71 (2004)).
There are currently at least nine known members of the family of voltage-gated sodium channel (VGSC) alpha subunits. Names for this family include SCNx, SCNAx, and Navx.x. The VGSC family has been phylogenetically divided into two subfamilies Nav1.x (all but SCN6A) and Nav2.x (SCN6A). The Nav1.x subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX-sensitive or TTX-S) and those which are resistant to blocking by tetrodotoxin (TTX-resistant or TTX-R).
The Nav1.8 channel is a voltage-gated sodium channel which is expressed in nociceptors, the sensory neurones responsible for transducing painful stimuli. The rat channel and the human channel were cloned in 1996 and 1998 respectively (Nature 1996; 379: 257-262; Pain 1998(November); 78(2):107-114). The Nav1.8 channel was previously known as SNS (sensory neurone specific) and PN3 (peripheral nerve type 3). The Nav1.8 channel is atypical in that it shows resistance to the blocking effects of the puffer fish toxin tetrodotoxin and it is believed to underlie the slow-voltage-gated and tetrodotoxin-resistant (TTX-R) sodium currents recorded from dorsal root ganglion neurones. The closest molecular relative to the Nav1.8 channel is the Nav1.5 channel, which is the cardiac sodium channel, with which it shares approximately 60% homology. The Nav1.8 channel is expressed most highly in the ‘small cells’ of the dorsal root ganglia (DRG). These are thought to be the C- and A-delta cells which are the putative polymodal nociceptors, or pain sensors. Under normal conditions, the Nav1.8 channel is not expressed anywhere other than subpopulations of DRG neurones. The Nav1.8 channels are thought to contribute to the process of DRG sensitisation and also to hyperexcitability due to nerve injury. Inhibitory modulation of the Nav1.8 channels is aimed at reducing the excitability of nociceptors, by preventing them from contributing to the excitatory process.
Studies have shown that Nav1.8 knock-out leads to a blunted pain phenotype, mostly to inflammatory challenges (A. N. Akopian et al., Nat. Neurosci. 1999; 2; 541-548) and that Nav1.8 knockdown reduces pain behaviours, in this case neuropathic pain (J. Lai et al., Pain, 2002(January); 95(1-2): 143-152). Coward et al. and Yiangou et al., have shown that Nav1.8 appears to be expressed in pain conditions (Pain. 2000(March); 85(1-2): 41-50 and FEBS Lett. 2000(February 11); 467(2-3): 249-252).
The Nav1.8 channel has also been shown to be expressed in structures relating to the back and tooth pulp and there is evidence for a role in causalgia, inflammatory bowel conditions and multiple sclerosis (Bucknill et al., Spine. 2002(January 15); 27(2):135-140: Shembalker et al., Eur J. Pain. 2001; 5(3): 319-323: Laird et al., J. Neurosci. 2002(October 1); 22(19): 8352-8356: Black et al., Neuroreport. 1999(April 6); 10(5): 913-918 and Proc. Natl. Acad. Sci. USA 2000:97:11598-11602).
Examples of modulators of the Nav1.8 sodium channel are disclosed in WO2008/135826, WO2008/135830, and WO2012/116440. There is, however, an ongoing need to provide new Nav1.8 sodium channel inhibitors that are good drug candidates. These drug candidates should have one or more of the following properties: be well absorbed from the gastrointestinal tract; be metabolically stable; have a good metabolic profile, in particular with respect to the toxicity or allergenicity of any metabolites formed; or possess favourable pharmacokinetic properties whilst still retaining their activity profile as Nav1.8 channel inhibitors. They should be non-toxic and demonstrate few side-effects. Ideal drug candidates should exist in a physical form that is stable, non-hygroscopic and easily formulated.